6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide → 6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide

HRID 1528217Notes

Reaction equation

HRID 1528217 reaction equation
[CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:31](=O)[C:30](=[O:33])[C:29]=2[O:34]CC)=[CH:17][CH:16]=1>CO>[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:29](=[O:34])[C:30](=[O:33])[C:31]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:17][CH:16]=1

Participants

4

Reactant 2

HCID 895255256-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamideHCID 89525580C-(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine

Product 1

HCID 715259756-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamideYield 53%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of 412 mg (2.27 mmol, 1.1 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 700 mg (2.07 mmol, 1 eq) of 6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide in 45 ml of methanol was stirred at ambient temperature for 3 days. The methanol was evaporated off and the residue was taken up with ethyl acetate and washed with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue (0.90 g) was chromatographed on silica gel (80 g prepacked column, eluent dichloromethane/methanol, from 0 to 10% of methanol). 520 mg of 6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained in the form of an ochre solid. Yield=53%. Mp=165-167° C.

Workup

  1. customThe methanol was evaporated off
  2. washwashed with a 1 M aqueous sodium dihydrogen phosphate solution
  3. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue (0.90 g) was chromatographed on silica gel (80 g prepacked column, eluent dichloromethane/methanol, from 0 to 10% of methanol)

Sources & evidence

ORD record
ord-9de151fb976e4d98a7b2f3307e71b6df
Source dataset
uspto-grants-2015_07
Patent number
US09090596B2

Reaction notes

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